DE2647496A1 - NEW CEPHALOSPORIN DERIVATIVES - Google Patents

Description

The present invention relates to novel cephalosporin derivatives useful as antibiotics and processes for their preparation.

Compounds of the general formula I are suitable as antibiotics I wherein R [deep] 1 and R [deep] 2 are individually hydrogen or lower alkyl radicals with 1 to 4 carbon atoms or -NR [deep] 1R [deep] 2 is a pyrrolidino, piperidino or morpholino radical, R is oxygen or sulfur, aryl Phenyl or 2-thienyl radical, Y hydrogen, chlorine, bromine, a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms or lower alkoxy radical having 1 to 4 carbon atoms, with the proviso that, when aryl is the 2-thienyl radical, Y is hydrogen Z is a bond, oxygen, sulfur or the imino group, with the proviso that when aryl is the 2-thienyl radical, Z is a bond, W is hydrogen, the methyl group, amino group, hydroxyl group, sulfonic acid group or a radical COOR [deep] 3, where R [deep] 3 is hydrogen or the 5-indanyl radical, n is the number 0, 1 or 2, with the proviso that if W is different from hydrogen or methyl and Z is not a bond, n is not 0, R [deep] 4 hydrogen or the methoxy group, M water toff, a pharmaceutically acceptable non-toxic cation, an alkanoyloxymethyl radical with an alkanoyl moiety with 1 to 5 carbon atoms, which can be straight-chain or branched, an alkanoylaminomethyl radical with an alkanoyl moiety with 1 to 5 carbon atoms, which can be straight-chain or branched, with the amino nitrogen through an alkyl radical with 1 to 4 carbon atoms can be substituted, an alkoxycarbonylaminomethyl radical with an alkoxy moiety with 1 to 4 carbon atoms, which can be straight-chain or branched, the amine nitrogen can be substituted by an alkyl radical with 1 to 4 carbon atoms, a p-alkanoyloxybenzyl radical with a Alkanoyl moiety with 1 to 5 carbon atoms, which can be straight-chain or branched, or an aminoalkanoyloxymethyl radical with an alkanoyl moiety with 2 to 15 carbon atoms, wherein the amine nitrogen can be mono- or disubstituted by a lower alkyl radical with 1 to 4 carbon atoms, and

X is hydrogen, acetoxy, 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio, tetrazol-5-ylthio, 1-methyl-tetrazole 5-ylthio, 2-methyl-1,3,4-oxydiazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,2,3-triazol-5-ylthio represent, as well as their pharmaceutically acceptable salts.

From formula I it can be seen that the aryl radical is substituted by a thiocarbamatomethyl group, which is an aminothionomethylthiomethyl group of the formula or an aminocarbonylthiomethyl group of the formula wherein R [deep] 1 and R [deep] 2 have the meaning given in connection with formula I, can be.

In general formula I, the radical M can be composed of not only hydrogen or a pharmaceutically acceptable non-toxic cation but also an alkanoyloxymethyl radical of the formula consist, in which R [deep] 5 denotes a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms, an alkanoylaminomethyl or alkoxycarbonylaminomethyl radical of the formula

wherein R [deep] 6 is a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms or a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms and R [deep] 7 is hydrogen or a lower alkyl radical having 1 to 4 carbon atoms, a p-alkanoyloxybenzyl radical the formula wherein R [deep] 8 denotes a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms, or an aminoalkanoyloxymethyl radical of the formula wherein m is a number from 0 to 5, R [deep] 9 and R [deep] 10 are each hydrogen or lower alkyl radicals having 1 to 4 carbon atoms and R [deep] 11 and R [deep] 12 are hydrogen or straight-chain or branched lower alkyl radicals Mean 1 to 4 carbon atoms.

Examples of straight-chain or branched lower alkyl radicals with 1 to 4 carbon atoms, which can represent the symbols Y, R [deep] 5, R [deep] 6, R [deep] 8, R [deep] 11 and R [deep] 12, are the methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl radicals.

Examples of lower alkyl radicals with 1 to 4 carbon atoms, which can represent the symbols R [deep] 1, R [deep] 2, R [deep] 7, R [deep] 9 and R [deep] 10, are the methyl, Ethyl, n-propyl and n-butyl radical.

Examples of straight-chain or branched lower alkoxy radicals which can represent the symbol R [deep] 6 are methoxy, ethoxy, n-propoxy, isopropoxy, sec-butoxy and n-butoxy radical.

In general formula I, the substituent X can represent, in addition to hydrogen or the acetoxy radical, a sulfur-containing heterocyclic radical, namely 1,3,4-thiadiazol-5-ylthio, 3-methyl-1,2,4-thiadiazol-5-ylthio -, tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio - or 1,2,3-triazol-5-ylthio radical, which are represented by the following formulas:

If the aryl radical in the compounds of general formula I consists of the phenyl radical, then each of the thiocarbamatomethyl substituents and the substituent Y can be bonded individually in one of the positions 2 to 6 of the phenyl ring. Compounds of this type can be represented by the following general formula II: II

The preferred positions for the thiocarbamatomethyl substituent in formula II are the o- and p-positions of the phenyl ring. In formula II, the symbols R, R [deep] 1, R [deep] 2, X, Z, n, W, R [deep] 4, M and X have the meaning given in connection with formula I.

If the aryl radical in the compounds of general formula I is the 2-thienyl radical, then Y is hydrogen and Z is a bond. Compounds of this type are represented by the following formula III: III

In the compounds of the formula III, the thiocarbamatomethyl substituent can be bonded in the 4- or 5-position of the thienyl radical. The symbols R, R [deep] 1, R [deep] 2, n, W, R [deep] 4, M and X have the meaning given for formula I in connection with formula III.

In the compounds of the general formulas I to III, the substituent R [deep] 4 can be cis or trans to the hydrogen atom in the 6-position of the cephalosporin derivative. The compounds I to III in which the substituent R [deep] 4 is cis to the hydrogen atom mentioned are preferred.

Further preferred embodiments of the invention are:

(A) Compounds in which W is hydrogen, the hydroxyl, amino or sulfonic acid group or a radical COOR [deep] 3, in which R [deep] 3 is hydrogen. Such a substitution leads to compounds with a broader spectrum of activity and / or improved oral activity. Means e.g.

(1) W a hydroxyl group, the compounds are more resistant to beta-lactamase organisms,

(2) W a SO [deep] 3H or COOR [deep] 3 group, in which R [deep] 3 is hydrogen, the compounds have a broader spectrum against gram-negative microorganisms,

(3) If an NH [deep] 2 group, there is improved oral efficacy;

(B) Compounds in which R [deep] 4 represents a methoxy group are of particular interest because they develop antibacterial activity against cephalosporinase-producing gram-negative organisms;

(C) Compounds in which X is the acetoxy, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1-methyltetrazol-5-ylthio radical.

Most preferred according to the invention are compounds of the formula IV IV

wherein R, R [deep] 1 and R [deep] 2 have the meaning given for formula I and W 'is hydrogen, the hydroxyl group, amino group, carboxyl group or sulfonic acid group and X' is hydrogen, the acetoxy, 2-methyl-1,3 , 4-thiadiazol-5-ylthio or 1-methyltetrazol-5-ylthio radical represent, and their pharmaceutically acceptable salts.

Compounds of the formula IV in which the hydrogen atoms in the 6- and 7-positions are cis to one another are preferred.

The individual optical isomers of the compounds according to the invention in which W or W 'are different from hydrogen also fall within the scope of the invention.

The invention also includes the non-toxic inorganic acid addition salts of the above compounds such as mineral acid addition salts, for example the hydrochlorides, hydrobromides, hydroiodides, sulfates, sulfamates, phosphates, and also organic acid addition salts such as, for example, maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate , Fumarate, malate, mandelate and ascorbate.

The non-toxic pharmaceutically acceptable salts of compounds in which W is a carboxy or sulfonic acid group and of compounds in which M is hydrogen also fall within the scope of the invention. Examples of pharmaceutically acceptable salts of these acids are the salts with primary, secondary or tertiary amines such as cyolohexylamine, ethylamine and pyridine.

The pharmaceutically acceptable cations that can appear as the M radical in the compounds of the general formula I to III include alkali metal ions such as the sodium or potassium ion, the calcium ion and the ammonium ion, organic amine cations such as low-alkylammonium radicals such as the triethylammonium radical and the rest of N-ethylpiperidine.

The salts of the compounds I to III, in which M is a pharmaceutically acceptable cation, are prepared in a known manner and are formed in situ or by reacting the acid in question with a base such as sodium bicarbonate or triethylamine.

The compounds of the invention can be administered in a manner similar to the numerous known cephalosporin compounds, e.g., cephalexin, cephalothin, or cephaloglycine. They can be used alone or in the form of pharmaceutical preparations for oral or parenteral administration or topically to warm-blooded animals, i.e. birds and mammals, e.g. to cats, dogs, cattle, sheep and horses as well as to humans. For oral administration, the compounds are given in the form of tablets, capsules or pills or as elixirs or suspensions. For parenteral administration, it is best to prepare a sterile aqueous solution which may contain other solutes, e.g. enough common salt or glucose to make the solution isotonic. For topical administration, the compounds are incorporated into creams or ointments.

Examples of bacteria against which the compounds according to the invention act are Staphylococcus aureus, Salmonella schottmuelleri, Klebsiella pneumoniae, Diplococcus pneumoniae and Streptococcus pyogenes.

An example of a cephalosporin derivative according to the invention is 3 - [(acetoxy) methyl] -7 - [[2- [4 - [[(aminothioxomethyl) thio] methyl] phenyl] acetyl] amino] -8-oxo-5-thia-1 -azabicyclo [4.2.0] oct-2-en-2-carboxylic acid. Further examples of compounds according to the invention are given below.

The compounds according to the invention in which R [deep] 3 is hydrogen are prepared by coupling 7-aminocephalosporanic acid or a derivative of the formula V V

wherein R [deep] 4, M and X have the meaning given above, with an acid of the formula VI or a functional derivative thereof:

VI

where R, R [low] 1, R [low] 2, aryl, Y, Z and n have the meaning given above and W [high] 2 denotes hydrogen, the methyl group, amino group, hydroxyl group, sulfonic acid group or carboxyl group. If the substituent W [high] 2 in formula VI is an amino group, then suitable protective groups, e.g. an acid salt such as the hydrochloride, an acyl radical or the tert-butoxycarbonyl radical, can be used to protect the amino function. These protecting groups are removed after the coupling reaction in a known manner, for example as described in U.S. Patent 3,657,232.

Functional equivalents of the acids VI include the acid halides, e.g., the acid chloride, the acid anhydrides including mixed anhydrides with e.g. Furthermore, you can use the acid azide or an active ester or thioester, for example with p-nitrophenol, 2,4-dinitrophenol or thioacetic acid, or you can couple the free acid of the formula VI with the 7-aminocephalosporanic acid derivative of the formula V, after first having the Has reacted acid with N, N'-dimethylchloroformium chloride, or using a carbodiimide reagent such as N, N'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide or N-cyclohexyl-N '- (2-morpholinoethyl) carbodiimide. A preferred method is to use an acid anhydride such as the anhydride formed with pivalic acid.

The coupling reaction is generally carried out in the presence of a solvent. Suitable solvents include ethyl acetate, acetone, dioxane, acetonitrile, chloroform, ethylene chloride, tetrahydrofuran and dimethylformamide. Since hydrophilic solvents are used, mixtures of these solvents and water can also be used in the above reactions. The coupling reaction is generally carried out in the presence of a base such as an alkali bicarbonate. The reaction temperature can be between -10 and 100 ° C, the reaction time is about 1/2 to 10 hours. With an anhydrous solution of the compound of the formula V, higher yields are achieved. The cephalosporin products are isolated using conventional methods.

Compounds of the formula V in which R [deep] 4 is hydrogen, M is hydrogen or a pharmaceutically acceptable non-toxic cation and X is hydrogen or the acetoxy group, are commercially available or can be prepared by known methods. The compounds in which R [deep] 4 is the methoxy group can be prepared according to the general procedure of US Pat. No. 3,778,432.

Compounds of the formula V in which M denotes an alkanoyloxymethyl radical are obtained by reacting the acid in question in the form of a salt, for example an alkali metal or triethylammonium salt, with a compound of the formula in which halo is chlorine or bromine and R [deep] 5 is a straight or branched chain lower alkyl radical having 1 to 4 carbon atoms, using the general procedure of US Pat. No. 3,655,658.

Compounds of the formula V, in which M is an alkanoylaminomethyl radical or alkoxycarbonylaminomethyl radical, are obtained by reacting the sodium salt of acid derivatives of the formula V in an organic solvent such as dimethylformamide or hexamethylphosphoramide at room temperature with an equivalent amount of an alkanoylaminomethyl halide or an alkoxycarbonylaminomethyl halide for 1/2 to 3 hours treated and then pour the mixture into ice water. The resulting precipitate, which consists of the product, is isolated using standard procedures.

Compounds of the formula V in which M is a p-alkanoyloxybenzyl radical are prepared by adding 2 equivalents of p-alkanoyloxybenzyl alcohol to a suspension of the sodium salt of acid V in dimethylformamide or hexamethylphosphoramide, whereupon the mixture is cooled to 0 ° C. Then 1.2 equivalents of dicyclohexylcarbodiimide and dimethylformamide are added dropwise with stirring. The mixture is stirred at 0 ° C. for 1/2 to 3 hours and then at room temperature for a further 2 to 5 hours. The resulting dicyclohexylurea is filtered off and the filtrate is diluted with chloroform, methylene chloride or ethyl acetate, washed with water and dried to give the product.

Compounds of the formula V in which M is an aminoalkanoyloxymethyl radical are prepared by mixing a suspension of the sodium salt of an acid of the formula V with an excess of the aminoalkanoyloxymethyl halide in question with a protected amino group in a solvent such as dimethylformamide, hexamethylphosphoramide or dimethyl sulfoxide for 2 to 96 hours. The mixture is then diluted with a solvent such as ethyl acetate or methylene chloride and then washed with water, aqueous base and water. The organic phase is separated and the precipitate is isolated in a conventional manner, whereupon the protecting groups are removed and the product is obtained.

Compounds of the formula V, in which X is a sulfur-containing heterocyclic radical, are obtained by adding 1 equivalent of the acid in the form of a salt, for example the sodium salt, in which X is the acetoxy radical, in about 500 to 2000 ml of water at 50 to 80 ° C Dissolves under a nitrogen atmosphere and then 1 equivalent of a base such as triethylammonium or sodium bicarbonate and 1 to 3 equivalents of the relevant heterocyclic compound of the following formula: clogs.

Compounds of the general formula VI are prepared by adding a compound of the formula VII VII

where halo is chlorine or bromine and aryl, Y, Z, n and W [high] 2 have the meaning given above, with a thio or dithiocarbamate salt of the formula VIII

VIII

where R [deep] 1 and R [deep] 2 are hydrogen or lower alkyl radicals with 1 to 4 carbon atoms and R is oxygen or sulfur, in a solvent such as a lower alcohol such as methanol, ethanol, isopropyl alcohol or n-butanol or in dimethyl sulfoxide, Dimethylformamide or an aqueous mixture of these solvents for 1/2 to 24 hours at 0 to 125 ° C treated. The products can be isolated using conventional methods. In some cases it may be more advantageous to convert the acid of the formula VII into the methyl ester concerned, e.g. by treating the acid with diazomethane at -10 ° C and stirring the mixture for about 10 to 30 minutes at room temperature. Suitable salts of compounds of the formula VIII are the metal salts of metals of group IA, for example the sodium and potassium salts, amine and dialkylamine salts such as the salts with dimethylamine and diethylamine, furthermore with pyrrolidine, piperidine and morpholine.

If W [high] 2 in compounds of the general formula VIII is an amino group, it is protected by a suitable protective group, for example the tert-butoxycarbonyl radical, before treatment with the carbamate salt of the formula VIII. The protective group can be mildly acidic after the coupling reaction Hydrolysis or hydrogenolysis can be removed in a known manner.

Compounds of general formula VIII are commercially available or known, or they can be prepared by the methods of E. Emmet Reid, Organic Chemistry of Bi-Valent Sulfur, Chemical Publishing, Co., New York, 1962, Vol. IV, p. 196 and J. Parrod, Compt. rend, 234, 1062 (1952).

The compounds of formula VII are prepared by direct halomethylation of an acid of formula IX IX

wherein aryl, Y, Z, n and W [high] 2 are as defined above, in the manner described below. The compounds IX are commercially available or can be prepared by known methods.

If the substituent W [high] 2 in the compound IX is an amino group, this is protected by a suitable protective group, as described in connection with the compounds of the formula VII.

The halomethylated derivatives of the compounds of the formula IX can be obtained by several methods. For example, from a compound of the formula IX and a formaldehyde source such as paraformaldehyde, ClCH [deep] 2OCH [deep] 3 or formalin solution in the presence of a Lewis acid such as ZnCl [deep] 2, AlCl [deep] 3, SnCl [deep] 4 or ClSO [deep] 3H in a solvent such as petroleum ether, chloroform, carbon tetrachloride or benzene at a temperature of -10 to 100 ° C. with the introduction of hydrogen chloride gas or hydrogen bromide gas into the reaction mixture, compounds of the formula VII.

The compounds of the general formula VII are also obtained by reacting an acid of the formula IX with 34 to 38% strength formalin in concentrated hydrochloric acid at temperatures of -10 ° to 100 ° C. while passing hydrogen chloride or hydrogen bromide gas through the reaction mixture.

Furthermore, compounds of the general formula VII are obtained through the reaction mixture by reacting an acid of the formula IX with trioxane in acetic acid or phosphoric acid at temperatures from -10 to 100 ° C. with the introduction of hydrogen chloride or hydrogen bromide. Furthermore, the reaction of an acid of the formula IX in the presence of a Lewis acid of the type described above with chloromethyl ether at temperatures of -10 to 100 ° C. or the reaction of the acid in acetic acid or concentrated sulfuric acid with dichloromethyl ether in the presence of zinc chloride leads to compounds of the general type Formula VII.

The compounds of the formula VII, in which W [high] 2 is the carboxyl group and aryl is the phenyl radical, are preferably obtained by treating the relevant diethyl ester of the formula IX with 40% formalin in the presence of anhydrous zinc chloride in benzene at about 50.degree Introducing hydrogen chloride or hydrogen bromide into the reaction mixture, followed by acid hydrolysis.

Compounds of the formula VII, in which W [high] 2 denotes the sulfonic acid group, can be prepared by the halomethylation process described using an acid of the formula IX, in which W [high] 2 denotes the sulfonic acid group or its carboxymethyl ester, in the latter case the resulting halomethylated Compound is converted into the free carboxylic acid by acid hydrolysis.

In the halomethylation of compounds of the formula IX in which W [high] 2 is the hydroxyl group, it may be advisable to protect this hydroxyl group from halomethylation according to B. Reichert, et al., Pharmazie 5, 10 (1950).

Compounds according to the invention in which R [deep] 3 denotes the 5-indanyl radical are obtained by reacting the acid in question, that is, compounds of the general formula I in which R [deep] 3 denotes hydrogen, with 5-indanol in an inert solvent in the presence of N, N'-dicyclohexylcarbodiimide at pH about 2.5 and a temperature of about 20 to 30 ° C. Equimolar amounts of the reactants or a slight excess of 5-indanol are used. The molar amount of N, N'-dicyclohexylcarbodiimide corresponds to the molar amount of 5-indanol. Suitable solvents for the reaction are dioxane, tetrahydrofuran, ethyl acetate, dimethylformamide and methylene chloride.

The compounds according to the invention can also be prepared by linking a modified polystyrene containing nitrophenol or hydroxylsuccinimide groups with an acid of the general formula VI according to the general rule of CA-PS 892 580, the penicillanic acid derivative used there being linked by a compound of the general formula V. replaced.

Compounds according to the invention in which X is a sulfur-containing heterocyclic 1,3,4-thiadiazol-5-ylthio-, 3-methyl-1,2,3-thiadiazol-5-ylthio-, tetrazol-5-ylthio-, 1-methyl- tetrazol-5-ylthio-, 2-methyl-1,3,4-oxadiazol-5-ylthio-, 2-methyl-1,3,4-thiadiazol-5-ylthio- or 1,2,3-triazol-5 -ylthio radical and M represent hydrogen can be prepared by reacting the 3 - [(acetyloxy) methyl] derivative with the relevant heterocyclic thiol according to the following equation:

X XI

In the above formulas X and XI, R, R [deep] 1, R [deep] 2, aryl, Y, Z, n, W and R [deep] 4 have the meaning given in connection with formula I, the S hetero radical consists of a 1,3,4-thiadiazol-5-ylthio-, 3-methyl-1,2,4-thiadiazol-5-ylthio-, tetrazol-5-ylthio-, 1-methyltetrazol-5-ylthio-, 2 -Methyl-1,3,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,2,3-triazol-5-ylthio.

In the above reaction, 1 equivalent of the sodium salt of compound X is dissolved in water at 25 to 90 ° C under a nitrogen atmosphere, then 1 equivalent of a base such as triethylamine or sodium bicarbonate and 1 to 3 equivalents of the heterothiol are added, whereupon the reaction mixture is about 2 to 6 Hours at 25 to 90 ° C is stirred.

Compounds according to the invention in which M is an alkanoylaminomethyl or alkoxycarbonylaminomethyl radical and W is not a carboxyl group can also be prepared by adding the acid in question in the form of a salt such as an alkali metal salt, for example the sodium salt, with 1.5 to 2.5 equivalents of the relevant alkanoylaminomethyl halide or alkoxycarbonylaminomethyl halide of the formula converts, wherein halo is a reactive halogen atom such as chlorine or bromine, R [deep] 6 is a straight-chain or branched lower alkyl radical with 1 to 4 carbon atoms or a straight-chain or branched lower alkoxy radical with 1 to 4 carbon atoms and R [deep] 7 is hydrogen or a lower one Represent an alkyl radical having 1 to 4 carbon atoms. The reactants are stirred in dimethylformamide, hexamethylphosphoramide or a similar solvent at a temperature of 10 to 45 ° C. for about 1 to 5 hours, then the reaction mixture is poured into ice water and decanted. The oily residue is taken up in an organic solvent such as ethyl acetate, methylene chloride or benzene, washed with a base and then with water and dried over magnesium sulfate. The organic solution is concentrated to dryness in vacuo to give the desired ester.

Before the esterification, compounds in which W denotes an amino group are provided with protective groups, such as, for example, the tert-butoxycarbonyl radical or the carbobenzyloxy radical, these groups being removed in a known manner after the esterification has ended, see, for example, the processes of the US Pat 3 657 232.

Compounds according to the invention in which M is a p-alkanoyloxybenzyl radical and W is not a carboxyl group can also be prepared by reacting molar equivalents of the acid in question with a p-alkanoyloxybenzyl alcohol, the alkanoyl radical of which has 1 to 4 carbon atoms and can be straight-chain or branched. The reactants are dissolved in an organic solvent such as dimethylformamide or hexamethylphosphoramide, the solution is cooled to a temperature of -15 to 25 ° C., then an equivalent amount of dicyclohexylcarbodiimide in dimethylformamide or hexamethylphosphoramide is added dropwise with stirring. The mixture is stirred for a further 1/2 to 2 hours at -15 to 25 ° C. and then for 4 to 6 hours at 25 to 45 ° C. The resulting dicyclohexylurea is filtered off, the filtrate is diluted with chloroform, ethyl acetate or methylene chloride and washed with water. The organic phase is dried and concentrated, whereby the product is obtained.

Compounds according to the invention in which M is an alkanoyloxymethyl radical and W is not a carboxyl group can also be prepared by reacting the acid in question in the form of a salt, for example an alkali metal or triethylammonium salt, with a compound of the formula wherein halo is chlorine or bromine and R [deep] 5 is a straight or branched chain alkyl radical having 1 to 4 carbon atoms, using the general procedure of US Pat. No. 3,655,658.

Compounds according to the invention in which M is an aminoalkanoyloxymethyl radical and W is not a carboxyl group can be prepared by adding a suspension of the sodium salt of the acid in question with an excess of the aminoalkanoyloxymethyl halide in question with a protected amino group in a solvent such as dimethylformamide, hexamethylphosphoramide or dimethyl sulfoxide for 2 to 96 hours mixes. The mixture is then diluted with a solvent such as ethyl acetate or methylene chloride and washed with water, aqueous base and then with water. The organic phase is separated off and the precipitate is isolated in a conventional manner, whereupon the amino-protecting group is removed and the product is obtained.

Compounds according to the invention in which R [deep] 3 denotes the carboxyl group can also be prepared by solvolysis of a compound of the formula XII XII

wherein aryl, Y, Z, n, R [deep] 4, M and X have the meaning given in connection with formula I, halo chlorine or bromine and W [high] 2 hydrogen, the methyl, amino, hydroxy, Sulphonic acid or carboxyl group with a compound of the general formula VIII or a salt thereof in a solvent such as a lower alcohol such as methanol, ethanol, isopropyl alcohol, n-butanol or in dimethyl sulfoxide, dimethylformamide or aqueous mixtures of these solvents. The reaction is carried out for 1/2 to 24 hours at temperatures from 0 to 125 ° C., and the products are isolated by conventional methods. This method is less preferred when the solution of the salt of the compound of formula VIII is strongly basic.

Compounds of the formula XII are obtained by coupling a compound of the formula VII or a reactive derivative thereof with a compound of the formula V in a conventional manner.

example 1

p-chloromethylphenylacetyl chloride

(A) At a temperature of -10 to 0 ° C, hydrogen chloride is passed with stirring through a mixture of 102 g of phenylacetic acid, 67.5 g of paraformaldehyde and 67.5 g of zinc chloride in 1000 ml of petroleum ether for 1 hour. The mixture is then stirred for a further 1 hour at room temperature, then the mixture is refluxed for about 2 hours while hydrogen chloride gas is passed in. 1000 ml each of methylene chloride and water are then added to the reaction mixture. The organic phase is separated off and the aqueous phase is extracted twice with methylene chloride. The combined organic extracts are extracted four times with saturated sodium bicarbonate solution. The neutral organic phase is dried over anhydrous sodium sulphate, filtered and freed from the solvent in vacuo, a neutral by-product which is identified in more detail in Example 5 being obtained. The aqueous basic phase is separated off and acidified to pH 2 to 3 with cold concentrated hydrochloric acid, then extracted three times with methylene chloride. The methylene chloride fraction is dried over anhydrous sodium sulfate, filtered and freed from the solvent. The resulting oily acidic product is chromatographed on silica gel, eluting with benzene and benzene / acetone, the p-chloro methylphenylacetic acid is obtained, which is recrystallized from hot chloroform. M.p. 147 to 149 ° C.

(B) A mixture of 1 g of p-chloromethylphenylacetic acid and 6 ml of thionyl chloride is stirred at room temperature for 25 hours, then excess thionyl chloride is removed in vacuo to give p-chloromethylphenylacetyl chloride.

If an acid according to Table I is used instead of the phenylacetic acid in Example 1 (A), the chloromethyl derivative also listed in Table I is obtained, which can be converted into the acid chloride by the method of Example 1 (B).

Table I.

Acid chloromethyl derivative

Hydrotropic acid p-chloromethylhydrotropic acid

Mandelic acid p-chloromethylmandelic acid

Dihydrocinnamic acid p-chloromethyl dihydrocinnamic acid

2-methylhydrocinnamic acid p-chloromethyl-2-methyl-hydro-

cinnamic acid

3-phenyllactic acid 3- (p-chloromethylphenyl) -milk-

acid

4-phenylbutyric acid 4- (p-chloromethylphenyl) -

butyric acid

2-methyl-4-phenyl-2-methyl-4- (p-chloromethyl-

butyric acid (phenyl) butyric acid

2-hydroxy-4-phenyl- 2-hydroxy-4- (p-chloromethyl-

butyric acid (phenyl) butyric acid

Phenoxyacetic acid p-chloromethylphenoxy-

acetic acid

2-phenoxypropionic acid 2- (p-chloromethylphenoxy) -

propionic acid

Acid chloromethyl derivative

4-phenoxybutyric acid 4- (p-chloromethylphenoxy) -

butyric acid

2-methyl-4-phenoxy- 2-methyl-4- (p-chloromethyl-

butyric acid phenoxy) butyric acid

3-phenoxypropionic acid 3- (p-chloromethylphenoxy) -

propionic acid

3-phenoxy lactic acid 3- (p-chloromethylphenoxy) -

lactic acid

Anilinoacetic acid p-chloromethylanilino-

acetic acid

2-hydroxy-2- (2-thienyl) - 2-hydroxy-2- [2- (5-chloromethyl) -

acetic acid thienyl] acetic acid

2-anilinopropionic acid 2- (p-chloromethyl) anilino-

propionic acid

4-anilinobutyric acid 4- (p-chloromethylanilino) -

butyric acid

3-anilinobutyric acid 3- (p-chloromethylanilino) -

butyric acid

Phenylthioacetic acid p-chloromethylphenyl-

thioacetic acid

2-phenylthiopropion- 2- (p-chloromethylphenyl) -

acid thiopropionic acid

4-phenylthiobutyric acid 4- (p-chloromethylphenyl) -

thiobutyric acid

o-chlorophenyl- o-chloro-p-chloromethyl-

acetic acid phenylacetic acid

Example 2

p-chloromethylphenylglycine

A mixture of 2.03 g of trifluoroacetylated phenylglycine and 0.8 g of zinc chloride in chloromethyl ether is maintained for 12 hours

65 ° C heated. Excess reagent is removed in vacuo and the residue is dissolved in methylene chloride, the solution is washed with saturated sodium bicarbonate solution and then with saturated sodium chloride solution. The neutral organic phase is dried over sodium sulfate and concentrated to an oil, which is purified by column chromatography, the methyl ester of p-chloromethylphenylglycine being obtained, from which the acid hydrochloride is formed by hydrolysis with aqueous hydrochloric acid. The hydrochloride is then converted to the free base by adjusting the pH of the aqueous solution to about 5. The chloromethyl derivatives according to the following Table II are obtained in the same way from the specified acids:

Table II

Acid chloromethyl derivative

Phenylalanine p- (chloromethylphenyl) -

alanin

2-amino-4-phenyl- 2-amino-4- (p-chloromethyl-

butyric acid (phenyl) butyric acid

2-amino-4-phenoxy-2-amino-4- (p-chloromethyl-

butyric acid phenoxy) butyric acid

3-phenoxyalanine 3- (p-chloromethylphenoxy) -

alanin

2-amino-4-anilino- 2-amino-4- (p-chloromethylanilino) -

butyric acid butyric acid

2-amino-4-phenyl- 2-amino-4- (p-chloromethylphenyl) -

thiobutyric acid thiobutyric acid

3-phenylthioalanine 3- (p-chloromethylphenyl) -

thioalanine

2- (2-thienyl) glycine 2- [2- (5-chloromethyl) -

thienyl] glycine

Table II (Forsts.)

2-Amino-3- (2-thienyl) - 2-Amino-3- [2- (5-chloromethyl) -

propionic acid thienyl] propionic acid

2-amino-4- (2-thienyl) - 2-amino-4- [2- (5-chloromethyl) -

butyric acid thienyl] butyric acid

Example 3

p-chloromethylphenylmalonic acid

If, in the process of Example 1 (A), the equivalent amount of diethyl phenylmalonate is used instead of the phenylmalonic acid, the diethyl p-chloromethylphenylmalonate is obtained, from which the acid in question is obtained by acid hydrolysis. The chloromethyl derivatives listed in Table III are obtained in the same way if the diethyl ester of the specified acid is used instead of the phenylmalonic acid diethyl ester:

Table III

Acid chloromethyl derivative

2-sulfophenylacetic acid 2-sulfo-p-chloromethyl-

phenylacetic acid

3-phenyl-2-sulfopropion- 3- (p-chloromethylphenyl) -

acid 2-sulfopropionic acid

4-phenyl-2-sulfobutter- 4- (p-chloromethylphenyl) -

acid 2-sulfobutyric acid

Benzylmalonic acid p-chloromethylbenzyl-

malonic acid

Phenethylmalonic acid p-chloromethylphenethyl

malonic acid

2-phenoxyethylmalon- 2- (p-chloromethylphenoxy) -

acid ethylmalonic acid

2-phenylthioethylma- 2- (p-chloromethylphenyl) -

ionic acid thioethylmalonic acid

Table III (Forsts.)

Anilinomethylmalon- p-chloromethylanilino-

acid methylmalonic acid

2-thienylmalonic acid 2- [2- (5-chloromethyl) -

thienyl] malonic acid

2-thenylmalonic acid 2- [2- (5-chloromethyl) -

thenyl] malonic acid

Example 4

5- (chloromethyl) -2-thienylacetic acid

2-Thiophenecarboxylic acid is treated with chloromethyl ether in chloroform solution in the presence of 0.9 to 2.2 equivalents of aluminum chloride to give 5-chloromethyl-2-thienylcarboxylic acid. The acid chloride is obtained from this acid with excess thionyl chloride at room temperature in about 16 hours, which with diazomethane gives the relevant diazoketone. A methanol solution of the diazoketone is irradiated under nitrogen for about 1 hour with a high pressure mercury lamp using a quartz filter. After working up the mixture and column chromatography on silica gel, methyl 5-chloromethyl-2-thienylacetate is obtained. This acetate is hydrolyzed with a 1: 1 mixture of acetic acid and concentrated hydrochloric acid at room temperature overnight, 5-chloromethyl-2-thienylacetic acid being obtained.

Example 5

o-hydroxymethylphenylacetic acid lactone

The neutral by-product obtained in Example 1 is purified by vacuum sublimation (0.05 mm Hg at 80 ° C.), the title compound having a melting point of 82 ° C. being obtained.

Example 6

o-bromomethylphenylacetic acid

A solution of 0.55 g of o-hydroxymethylphenylacetic acid lactone in 2 ml of glacial acetic acid is added at 0 ° C. to a solution of 5 ml of glacial acetic acid saturated with hydrogen bromide gas. The mixture is stirred at room temperature for 2 hours and then refluxed for 1 hour, during which time hydrogen bromide gas is introduced. Excess lactone and solvent are removed in a high vacuum at room temperature. The resulting oily residue is triturated three times with hexane, o-bromomethylphenylacetic acid having a melting point of 110 ° C. is obtained.

Example 7

o-chloromethyl-p-methoxymandelic acid chloride

The above acid is prepared according to the method of B. Reichert et al., Pharmazie 5, 10 (1950) and converted into the acid chloride by treatment with thionyl chloride.

Example 8

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid propionyloxymethyl ester

7.5 g of the sodium salt of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid are added to 35 ml of dimethylformamide and the The solution is stirred for about 30 minutes at room temperature, then 8 ml of chloromethyl propionate are added. The mixture is then stirred for about 3 hours at room temperature, then the mixture is diluted with ethyl acetate and washed with water. The organic phase is separated off and concentrated to dryness. The residue is recrystallized from ethyl acetate, thereby obtained the 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid propionyloxymethyl ester.

If the chloromethyl propionate is replaced by the corresponding amount of chloromethyl pivalate, chloromethyl acetate or chloromethyl butyrate, the following products are obtained:

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid pivalyloxymethyl ester,

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid acetyloxymethyl ester,

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid butyryloxymethyl ester.

Example 9

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid 2-amino-3-methylbutyryloxymethyl ester

A suspension of 5 g of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid sodium salt and 8.5 g of N-tert .-Butoxycarbonyl-L-valine-chloromethyl ester (prepared according to the general procedure of DOS 2 236 620) are mixed in 100 ml of dimethylformamide and stirred for 72 hours. The mixture is diluted with ethyl acetate and washed with water, aqueous bicarbonate solution and again with water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness, the 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid-N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester, from which the title compound is obtained in the usual way after removal of the amino protective group.

Example 10

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid N-ethoxycarbonyl-N-methylaminomethyl ester

725 mg (2.5 millimoles) of the sodium salt of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid in 50 ml of dimethylformamide are treated at room temperature with 375 mg (2.5 millimoles) of N-chloromethyl-N-methyl urethane for 1 hour. The mixture is carefully poured into ice water and the precipitated solid is filtered off and washed with water. It is dissolved in ethyl acetate and the solution is washed with aqueous sodium bicarbonate solution and then with water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness in vacuo, the 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene being obtained -2-carboxylic acid N-ethoxycarbonyl-N-methylaminomethyl ester is obtained.

If in the above process the N-chloromethyl-N-methyl urethane is replaced by the corresponding amount of N-methyl-N-propionylaminomethyl chloride, N-butyrylaminomethyl chloride, N-acetylaminomethyl chloride or N-methyl-N-ethoxycarbonylaminomethyl chloride, the following compounds are obtained:

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid N-methyl-N-propionylaminomethyl ester,

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid N-butyrylaminomethyl ester,

3- (Acetoxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid N-acetylaminomethyl ester and

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid N-methyl-N-ethoxycarbonylaminomethyl ester.

Example 11

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid p-pivalyloxybenzyl ester

Add to a suspension of 6.6 millimoles of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid sodium salt in 35 ml of dimethylformamide 2 equivalents of p-pivalyloxybenzyl alcohol are added, the mixture is then cooled to 0 ° C., whereupon 7.2 millimoles of dicyclohexylcarbodiimide in 7.5 ml of dimethylformamide are added dropwise with stirring. The mixture is stirred for 1 hour at 0 ° and for a further 4 hours at room temperature, then the dicyclohexylurea is filtered off. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo, the 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid p-pivalyloxybenzyl ester is obtained.

If the p-pivalyloxybenzyl alcohol is replaced by the corresponding amount of p- (propionyloxy) benzyl alcohol, p- (acetyloxy) benzyl alcohol or p- (valeryloxy) benzyl alcohol in the above process, the following products are obtained:

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid p- (propionyloxy) benzyl ester,

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid p- (acetyloxy) benzyl ester and

3- (Acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid p- (valeryloxy) benzyl ester.

Example 12

3 - [(2-Methyl-1,3,4-thiadiazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid

In about 1 liter of water, 0.1 mol of the sodium salt of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid at 70 ° C dissolved under nitrogen. 1 equivalent of sodium bicarbonate and 2 equivalents of 2-methyl-1,3,4-thiadiazol-5-ylthiol are added to the solution. The mixture is stirred at 70 ° C. for 3 hours, then the pH is adjusted to 3.5. The resulting precipitate is collected, whereby the 3 - [(2-methyl-1,3,4-thiadiazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2. 0] oct-2-ene-carboxylic acid is obtained.

In the above process, the 2-methyl-1,3,4-thiadiazol-5-ylthiol is replaced by an equivalent amount of 1,3,4-thiadiazol-5-ylthiol, 3-methyl-1,2,4-thiadiazol-5 -ylthiol, tetrazol-5-ylthiol, 1-methyltetrazol-5-ylthiol, 2-methyl-1,3,4-oxadiazol-5-ylthiol or 1,2,3-triazol-5-ylthiol, the following products are obtained :

3 - [(1,3,4-Thiadiazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid,

3 - [(3-Methyl-1,2,4-thiadiazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid,

3 - [(Tetrazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid,

3 - [(1-Methyltetrazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid,

3 - [(2-Methyl-1,3,4-oxadiazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid and

3 - [(1,2,3-Triazol-5-ylthio) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid.

If, in the process of Example 8, corresponding amounts of 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and chloromethyl pivalate instead of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid and chloromethyl propionate are used, the 3-methyl-7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivalyloxymethyl ester is obtained.

Example 13

If, in the process of Example 12, corresponding amounts of the sodium salt of the cephalosporin derivative in question and heterocyclic thiols according to Table IV are used instead of the sodium salt of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 2-methyl-1,3,4-thiadiazol-5-ylthiol, the following products are obtained:

Table IV

Table IV (continued) Table IV (continued) Table IV (continued)

Example 14

p- (N, N-diethyldithiocarbamatomethyl) phenylacetic acid

A solution of 1.22 g (5.5 millimoles) of sodium diethyldithiocarbamate trihydrate and 463 mg (2.5 millimoles) of 4-chloromethylphenylacetic acid in 10 ml of methanol is stirred overnight at room temperature. The residue is dissolved in 15 ml of water, acidified to pH 1 with 10% aqueous hydrochloric acid and extracted with 50 ml of ether, then the extract is washed three times with water and dried over anhydrous magnesium sulfate. The ether is evaporated and the residue is recrystallized from ether / hexane, p- (N, N-diethyldithiocarbamatomethyl) phenylacetic acid having a melting point of 96 ° C. is obtained.

Example 15

p- (dithiocarbamatomethyl) phenylacetic acid

A solution of 75 mg (2.5 millimoles) of freshly prepared ammonium dithiocarbamate and 184.5 mg (1 millimole) of 4-chloromethylphenylacetic acid in 10 ml of methanol is stirred at room temperature under nitrogen. The solvent is evaporated and the residue is dissolved in water. The aqueous solution is acidified to pH 1 with aqueous hydrochloric acid and extracted with ethyl acetate, the extract is dried over magnesium sulfate and concentrated. The residue is recrystallized from ethyl acetate / hexane, giving p- (dithiocarbamatomethyl) phenylacetic acid with a melting point of 168 ° C.

Example 16

p- (Morpholinodithiocarbamatomethyl) phenylacetic acid

A solution of 1.85 g (0.01 mol) of 4-chloromethylphenylacetic acid and 6.25 g (0.025 mol) of freshly made morpholino dithiocarbamate salt in 250 ml of methanol is stirred under nitrogen at room temperature for 20 hours. The solvent is then evaporated off, water is added to the residue and the solution is acidified to pH 1 with 10% aqueous hydrochloric acid and then extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated, and the residue is recrystallized from ethyl acetate. This gives p- (morpholinodithiocarbamatomethyl) phenylacetic acid with a melting point of 163 ° C.

Example 17

p- (Morpholinomonothiocarbamatomethyl) phenylacetic acid

A modification of the synthesis by J. Parrod, Compt. rend. 234, 1062 (1952) the morpholine monothiocarbamate morpholine salt is produced. Carbonyl sulfide is passed through a trap cooled to -78 ° C in order to ensure the condensation of carbon disulfide, then the carbonyl sulfide is introduced into a solution of 8.7 g of morpholine in 150 ml of ethanol at 0 ° C. The precipitate is filtered off and washed with cold ethanol and the 7.5 g (0.032 mol) of the morpholine monothiocarbamate morpholine salt thus obtained are immediately combined with 1.85 g (0.01 mol) of chloromethylphenylacetic acid in 100 ml of dry methanol and combined for 20 hours under nitrogen touched. The methanol is then evaporated off, the residue is dissolved in water and acidified to pH 1 with aqueous 10% hydrochloric acid. It is then extracted with 400 ml of ethyl acetate and the extract is dried over anhydrous magnesium sulfate. The solvent is removed and the residue is recrystallized from ethyl acetate, p- (Morpholinomonothiocarbamatomethyl) phenylacetic acid having a melting point of 181 ° to 182 ° C. being obtained.

If the procedure of Example 14 is repeated, but replacing the sodium diethyldithiocarbamate trihydrate with the corresponding amount of the sodium salt of di-n-propyldithiocarbamate, di-n-butyldithiocarbamate, pyrrolidinodithiocarbamate or piperidinodithiocarbamate, the following acids are obtained:

p- (N, N-di-n-propyldithiocarbamatomethyl) phenylacetic acid,

p- (N, N-di-n-butyldithiocarbamatomethyl) phenylacetic acid,

p- (pyrrolidinodithiocarbamatomethyl) phenylacetic acid and

p- (piperidinodithiocarbamatomethyl) phenylacetic acid.

If the process of Example 17 is repeated, but replacing the morpholine monothiocarbamate morpholine salt with the corresponding amount of monothiocarbamate amine salt, dimethyl monothiocarbamate dimethylamine salt, diethyl monothiocarbamate diethylamine salt, di-n-propylmonothiocarbamate-di-n-propylmonothiocarbamate-di-butyl-monothiocarbamate-di-butyl-n-propylamine -butylamine salt, pyrrolidine monothiocarbamate pyrrolidine salt or piperidine monothiocarbamate piperidine salt, the following products are obtained:

p- (monothiocarbamatomethyl) phenylacetic acid,

p- (N, N-dimethylmonothiocarbamatomethyl) phenylacetic acid,

p- (N, N-diethylmonothiocarbamatomethyl) phenylacetic acid,

p- (N, N-di-n-propylmonothiocarbamatomethyl) phenylacetic acid,

p- (N, N-di-n-butylmonothiocarbamatomethyl) phenylacetic acid,

p- (pyrrolidinomonothiocarbamatomethyl) phenylacetic acid and

p- (piperidinomonothiocarbamatomethyl) phenylacetic acid.

If the process of Example 15 is repeated by reacting the corresponding amounts of the chloromethyl acid derivatives and carbamates listed in Table V with one another, the relevant amounts, also listed in Table V, are then reacted with one another

Carbamatomethyl-substituted acids obtained. Although other salts can be used, the sodium salt of carbamate is used with the exception that in the case of morpholinodi- and mono-thiocarbamate and piperidino-di- and mono-thiocarbamate, the relevant morpholine and piperidine salts are used:

Table V

Table V (continued) Table V (continued) Table V (continued) Table V (continued) Table V (continued)

Example 18

3- (Acetyloxymethyl) -7 - [[2- [4- (N, N-diethyldithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en -2-carboxylic acid

A solution of 289 mg (1 millimole) of p- (N, N-diethyldithiocarbamatomethyl) phenylacetic acid and 120 mg (1 millimole) of pivalyl chloride in absolute tetrahydrofuran is cooled to 0 ° C, then 101 mg (1 millimole) of triethylamine are added and the mixture is stirred for 30 minutes. A cold solution of 272 mg (1 millimole) 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 101 mg (1 millimole) of triethylamine in 7 ml of dry methylene chloride were added. The resulting mixture is stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour, then the solvent is removed in vacuo. The residue is dissolved in ice water, acidified to pH 2 with 10% hydrochloric acid and extracted with 30 ml of ethyl acetate. The organic phase is washed three times with water, dried over magnesium sulfate and concentrated to a residue, which is triturated with dry ether, crystallized from ethyl acetate and precipitated with a mixture of ether and hexane, the 3- (acetyloxymethyl) -7- [ [2- [4- (N, N-diethyldithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid of mp 138 to 140 ° C (decomposition).

Example 19

3- (Acetyloxymethyl) -7 - [[2- [4- (dithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

To a mixture of 60 mg (0.5 millimoles) of pivalyl chloride and 50.5 mg (0.5 millimoles) of triethylamine in 10 ml of dry tetra- hydrofuran is added to 120 mg (0.5 millimoles) of p- (dithiocarbamatomethyl) phenylacetic acid. The mixture is stirred for 30 minutes at 0 ° C., then a cold mixture of 136 mg (0.5 millimoles) 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0 ] oct-2-en-2-carboxylic acid and 75 mg (0.75 millimoles) of triethylamine in 7 ml of dry methylene chloride were added. The mixture is stirred for a further 30 minutes at 0 ° C. and for 1 hour at room temperature. The solvent is then evaporated off and 10 ml of cold water and 20 ml of ethyl acetate are added. The mixture is acidified to pH 2 with cold 10% hydrochloric acid and extracted with ethyl acetate. The organic phase is washed neutral with water, dried over magnesium sulfate and concentrated. The residue is washed with ether and recrystallized from ethyl acetate: ether / hexane to give the title compound.

Example 20

3- (Acetyloxymethyl) -7 - [[2- [4- (morpholinodithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

A cold solution of 544 mg (2 millimoles) 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 404 mg (4 Millimole) of triethylamine in 20 ml of methylene chloride is slowly stirred into a solution of the mixed anhydride of 622 mg (2 millimoles) of p- (morpholinodithiocarbamatomethyl) phenylacetic acid, 241 mg (2 millimoles) of pivalyl chloride and 202 mg (2 millimoles) of triethylamine in 20 ml of tetrahydrofuran of 0 ° C added. The mixture is stirred for a further 30 minutes at 0 ° C. and 1 hour at room temperature, then the solvent is evaporated off and cold water is added. The solution is acidified to pH 2 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated to a residue which is recrystallized from a hot mixture of 9 ml of chloroform, 9 ml of benzene and 2 ml of methanol. This gives 3- (acetyloxymethyl) -7 - [[2- [4- (morpholinodithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid with a melting point of 164 ° C (decomposition).

Example 21

3- (Acetyloxymethyl) -7 - [[2- [4- (morpholinomonothiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

A cold solution of 544 mg (2 millimoles) 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 404 mg (4 Millimole) of triethylamine in 20 ml of methylene chloride is slowly stirred into a solution of the mixed anhydride of 590 mg (2 millimoles) of p- (morpholinomonothiocarbamatomethyl) phenylacetic acid, 241 mg (2 millimoles) of pivalyl chloride and 202 mg (2 millimoles) of triethylamine in 20 ml of tetrahydrofuran of 0 ° C added. The mixture is stirred for a further 30 minutes at 0 ° C. and 1 hour at room temperature. The product is isolated according to the method described in Example 20, using the 3- (acetyloxymethyl) -7 - [[2- [4- (morpholinomonothiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-en-2-carboxylic acid with a melting point of 168 ° C.

If, in the process of Example 18, the p- (N, N-diethyldithiocarbamatomethyl) phenylacetic acid is replaced by the corresponding amount of an acid according to Table VI, the corresponding cephalosporin derivatives are obtained:

Table VI

Acid cephalosporin derivative

p- (N, N-di-n-propyldithio- 3- (acetyloxymethyl) -7 - [[2- [4-

carbamatomethyl) phenyl- (N, N-di-n-propyldithiocarbamato-

acetic acid methyl) phenyl] acetyl] amino] -

8-oxo-5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

p- (N, N-di-n-butyldithio- 3- (acetyloxymethyl) -7 - [[2-

carbamatomethyl) phenyl- [4- (N, N-di-n-butyldithio-

acetic acid carbamatomethyl) phenyl] ace-

tyl] amino] -8-oxo-5-thia-1-

azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

p- (Pyrrolidinothiocarbamato- 3- (acetyloxymethyl) -7 - [[2-

methyl) phenylacetic acid [4- (pyrrolidinodithiocarba-

matomethyl) phenyl] acetyl] -

amino] -8-oxo-5-thia-1-azabi

cyclo [4.2.0] oct-2-en-2-car-

boric acid

p- (Piperidinodithiocarbamato- 3- (acetyloxymethyl) -7 - [[2-

methyl) phenylacetic acid [4- (piperidinodithiocarba-

matomethyl) phenyl] acetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

p- (monothiocarbamatomethyl) - 3- (acetyloxymethyl) -7 - [[2-

phenylacetic acid [4- (monothiocarbamatomethyl) -

phenyl] acetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VI (cont.)

p- (N, N-dimethylmonothiocar- 3- (acetyloxymethyl) -7 - [[2-

bamatomethyl) phenylacetic acid [4- (N, N-dimethylmonothiocar-

bamatomethyl) phenyl] acetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

p- (N, N-diethylmonothio- 3- (acetyloxymethyl) -7 - [[2-

carbamatomethyl) phenyl- [4- (N, N-diethylmonothiocar-

acetic acid bamatomethyl) phenyl] acetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

p- (N, N-di-n-propylmono- 3- (acetyloxymethyl) -7 - [[2-

thiocarbamatomethyl) - [4- (N, N-di-n-propylmonothio-

phenylacetic acid carbamatomethyl) phenyl] ace-

tyl] amino] -8-oxo-5-thia-1-

azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

p- (N, N-di-n-butylmono- 3- (acetyloxymethyl) -7 - [[2-

thiocarbamatomethyl) - [4- (N, N-di-n-butylmonothio-

phenylacetic acid carbamatomethyl) phenyl] ace-

tyl] amino] -8-oxo-5-thia-1-

azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

p- (Pyrrolidinomonothio- 3- (acetyloxymethyl) -7 - [[2-

carbamatomethyl) phenyl- [4- (pyrrolidinomonothiocar-

acetic acid bamatomethyl) phenyl] acetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

Table VI (cont.)

p- (Piperidinomonothio- 3- (acetyloxymethyl) -7 - [[2-

carbamatomethyl) phenyl- [4- (piperidinomonothiocar-

acetic acid bamatomethyl) phenyl] acetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0.] oct-2-en-2-

carboxylic acid

p- (Dithiocarbamatomethyl) - 3- (acetyloxymethyl) -7 - [[2-

hydrotropic acid [4- (dithiocarbamatomethyl) -

phenyl] -2-methylacetyl] amino] -

8-oxo-5-thia-1-azabicyclo-

[4.2.0] oct-2-en-2-carboxylic acid

p- (N, N-dimethyldithiocar- 3- (acetyloxymethyl) -7 - [[2-

bamatomethyl) mandelic acid [4- (N, N-dimethyldithiocar-

bamatomethyl) phenyl] -2-hy-

droxyacetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

p- (N, N-diethyldithiocar- 3- (acetyloxymethyl) -7 - [[3-

bamatomethyl) dihydrocinnamon [4- (N, N-diethyldithiocarbam-

acid atomethyl) phenyl] propionyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

p- (N, N-di-n-propyldithio- 3- (acetyloxymethyl) -7 - [[3-

carbamatomethyl) -2-methyl- [5- (N, N-di-n-propyldithio-

hydrocinnamic acid carbamatomethyl) phenyl] -2-

methylpropionyl] amino] -8-

oxo-5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VI (cont.)

3- [p- (N, N-di-n-butyldi- 3- (acetyloxymethyl) -7 - [[3-

thiocarbamatomethyl) - [4- (N, N-di-n-butyldithiocar-

phenyl] lactic acid bamatomethyl) phenyl] -2-hy-

droxypropionyl] amino] -8-

oxo-5-thia-1-azabicyclo-

[4.2.0] oct-2-en-2-carboxylic acid

4- [p- (pyrrolidinodithio- 3- (acetyloxymethyl) -7 - [[4-

carbamatomethyl) phenyl] - [4- (pyrrolidinodithiocarbam-

butyric acid atomethyl) phenyl] butyryl] -

amino] -8-oxo-5-thia-1-azabi

cyclo [4.2.0] oct-2-en-2-car-

boric acid

2-methyl-4- [p- (piperi- 3- (acetyloxymethyl) -7 - [[4-

dinothiocarbamatomethyl) - [4- (piperidinodithiocarbam-

phenyl] butyric acid atomethyl) phenyl] -2-methyl-

butyryl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

2-hydroxy-4- [p- (morpholino- 3- (acetyloxymethyl) -7 - [[4-

dithiocarbamatomethyl) - [4- (morpholinodithiocarbam-

phenyl] butyric acid atomethyl) phenyl] -2-hydroxy-

butyryl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

p- (monothiocarbamatomethyl) - 3- (acetyloxymethyl) -7 - [[2-

phenoxyacetic acid [4- (monothiocarbamatomethyl) -

phenoxy] acetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VI (cont.)

2- [p- (N, N-dimethylmono- 3- (acetyloxymethyl) -7 - [[2-

thiocarbamatomethyl) - [4- (N, N-dimethylmonothiocar-

phenoxy] propionic acid bamatomethyl) phenoxy] -2-

methylacetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

4- [p- (N, N-diethylmono- 3- (acetyloxymethyl) -7 - [[4-

thiocarbamatomethyl) - [4- (N, N-diethylmonothiocar-

phenoxy] butyric acid bamatomethyl) phenoxy] butyryl] -

amino] -8-oxo-5-thia-1-azabi

cyclo [4.2.0] oct-2-en-2-carbon

acid

2-methyl-4- [p- (N, N-di-n-propyl- 3- (acetyloxymethyl) -7 - [[4-

monothiocarbamatomethyl) -phen- [4- (N, N-di-n-propylmonothio-

oxy] butyric acid carbamatomethyl) phenoxy] -2-

methylbutyryl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

3- [p- (N, N-di-n-butylmonothio- 3- (acetyloxymethyl) -7 - [[3-

carbamatomethyl) phenoxy] - [4- (N, N-di-n-butylmonothio-

propionic acid carbamatomethyl) phenoxy] -

propionyl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

3- [p- (pyrrolidinomonothiocar- 3- (acetyloxymethyl) -7 - [[3-

bamatomethyl) phenoxy] milk- [4- (pyrrolidinomonothiocar-

acid bamatomethyl) phenoxy] -2-hy-

droxypropionyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VI (cont.)

p- (Piperidinomonothiocarba- 3- (acetyloxymethyl) -7 - [[2-

matomethyl) anilinoacetic acid [4- (piperidinomonothiocar-

bamatomethyl) anilino] acetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

2-hydroxy-2- [5- (morpholino- 3- (acetyloxymethyl) -7 - [[2-

monothiocarbamatomethyl) -2- [5- (morpholinomonothiocar-

thienyl] acetic acid (bamatomethyl) -2-thienyl] -2-

hydroxyacetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

2- [p- (monothiocarbamatomethyl) - 3- (acetyloxymethyl) -7 - [[2-

anilino] propionic acid [4- (monothiocarbamatomethyl) -

anilino] -2-methylacetyl] am-

ino] -8-oxo-5-thia-1-azabi

cyclo [4.2.0] oct-2-en-2-

carboxylic acid

4- [p- (piperidinomonothiocar- 3- (acetyloxymethyl) -7 - [[4-

bamatomethyl) anilino] butter- [4- (piperidinomonothiocar-

acid bamatomethyl) anilino] butyryl] -

amino] -8-oxo-5-thia-1-azabi

cyclo [4.2.0] oct-2-en-2-

carboxylic acid

3- [p- (pyrrolidinomonothiocar- 3- (acetyloxymethyl) -7 - [[3-

bamatomethyl) anilino] butter- [4- (pyrrolidinomonothiocar-

acid (bamatomethyl) anilino] -2-

methylpropionyl] amino] -8-

oxo-5-thia-1-azabicyclo-

[4.2.0] oct-2-en-2-carbon

acid

Table VI (cont.)

p- (N, N-di-n-butylmonothio- 3- (acetyloxymethyl) -7 - [[2-

carbamatomethyl) phenylthio- [4- (N, N-di-n-butylmonothio-

acetic acid carbamatomethyl) phenylthio] -

acetyl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

2- [p- (N, N-di-n-propylmono- 3- (acetyloxymethyl) -7 - [[2-

thiocarbamatomethyl) phenyl] - [4- (N, N-di-n-propylmonothio-

thiopropionic acid carbamatomethyl) phenylthio] -

2-methylacetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

4- [p- (N, N-diethylmonothio- 3- (acetyloxymethyl) -7 - [[4-

carbamatomethyl) phenyl] - [4- (N, N-diethylmonothiocar-

thiobutyric acid (bamatomethyl) -phenylthio] bu-

tyryl] amino] -8-oxo-5-thia-1-

azabicyclo [4.2.0] oct-2-en-2-

carboxylic acid

p-chloro-p- (N, N-dimethylmono- 3- (acetyloxymethyl) -7 - [[2-

thiocarbamatomethyl) phenyl- [2-chloro-4- (N, N-dimethyl-

acetic acid monothiocarbamatomethyl) -

phenyl] acetyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid.

Example 22

3- (Acetyloxymethyl) -7 - [[2- [4- (monothiocarbamatomethyl) phenyl] -2-aminoacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en- 2-carboxylic acid

p-Monothiocarbamatomethyl-phenylglycine (made from the corresponding, above-described hydrochloride by treatment with a base), the amino group of which is protected by the tert-butoxycarbonyl radical, is treated with isobutyl chloroformate in the presence of triethylamine. Equimolar amounts of the mixed anhydride thus obtained and the triethylamine salt of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid are about 4 hours reacted with one another at 0 ° C. The resulting product is isolated and the amino protecting group is removed by acid hydrolysis, giving the 3- (acetyloxymethyl) -7 - [[2- [4- (monothiocarbamatomethyl) phenyl] -2-aminoacetyl] amino] -8-oxo-5 -thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid is obtained.

If in Example 22 the p-monothiocarbamatomethyl-phenylglycine is replaced by the relevant amount of an amino acid according to Table VII, the cephalosporin derivatives likewise shown in Table VII are obtained. The amino acids are prepared from the hydrochlorides as described above with a base.

Table VII

Amino acid cephalosporine derivative

p- (Morpholinodithiocarbama- 3- (acetyloxymethyl) -7 - [[3-

tomethyl) phenylalanine [4- (morpholinodithiocarbam-

atomethyl) phenyl] -2-amino-

propionyl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

2-Amino-4- [p- (piperidinodi- 3- (acetyloxymethyl) -7 - [[4-

thiocarbamatomethyl) phenyl] - [4- (piperidinodithiocarbam-

butyric acid atomethyl) phenyl] -2-amino-

butyryl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

Table VII (cont.)

2-amino-4- [p- (pyrrolidino- 3- (acetyloxymethyl) -7 - [[4-

dithiocarbamatomethyl) phen- [4- (pyrrolidinodithiocarbam-

oxy] butyric acid atomethyl) phenoxy] -2-amino-

butyryl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-

en-2-carboxylic acid

3- [p- (N, N-di-n-butyldithio- 3- (acetyloxymethyl) -7 - [[3-

carbamatomethyl) phenoxy] - [4- (N, N-di-n-butyldithiocar-

alanine (bamatomethyl) phenoxy] -2-

aminopropionyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

2-Amino-4- [p- (N, N-di-n-pro- 3- (acetyloxymethyl) -7 - [[4-

pyldithiocarbamatomethyl) - [4- (N, N-di-n-propyldithio-

anilino] butyric acid carbamatomethyl) anilino] -2-

aminobutyryl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

2-Amino-4- [p- (N, N-diethyldi- 3- (acetyloxymethyl) -7 - [[4-

thiocarbamatomethyl) phenyl] - [4- (N, N-diethyldithiocarbam-

thiobutyric acid atomethyl) phenylthio] -2-

aminobutyryl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

3- [p- (N, N-dimethyldithiocar- 3- (acetyloxymethyl) -7 - [[3-

bamatomethyl) phenyl] thioalanine [4- (N, N-dimethyldithiocar-

bamatomethyl) phenylthio] -2-

aminopropionyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VII (cont.)

2- [2- (5-dithiocarbamato- 3- (acetyloxymethyl) -7 - [[2-

methyl) thienyl] glycine [5- (dithiocarbamatomethyl) -

2-thienyl] -2-aminoacetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

2-Amino-3- [2- (5-dithiocar- 3- (acetyloxymethyl) -7 - [[3-

bamatomethyl) thienyl] - [5- (dithiocarbamatomethyl) -

propionic acid 2-thienyl] -2-aminopropionyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

2-Amino-4- [2- (5-N, N-dimethyl- 3- (acetyloxymethyl) -7 - [[4-

dithiocarbamatomethyl) thienyl] - [5- (N, N-dimethyldithiocar-

butyric acid bamatomethyl) -2-thienyl] -2-

aminobutyryl] amino] -8-oxo-5-

thia-1-azabicyclo [4.2.0] oct-

2-en-2-carboxylic acid.

Example 23

3- (Acetyloxymethyl) -7 - [[2- [4- (N, N-diethyldithiocarbamatomethyl) phenyl] -2-carboxyacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylic acid

Alpha-carboxy-pN, N-diethyldithiocarbamatomethylphenylacetyl-nitrophenyl polymer, prepared according to the method of CA-PS 892 580, which carries 4 millimoles of pN, N-diethyldithocarbamatomethylphenylmalonic acid, is suspended for 8 hours in a solution containing 20 ml of dry ethylene chloride and 1 Millimoles of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid triethylammonium salt (prepared from

544 mg (1 millimole) 7-aminocephalosphoranic acid and 0.56 mg (1 millimole) triethylamine at room temperature). As soon as only traces of 7-aminocephalosporanic acid remain in solution (determined by thin-layer chromatography on cellulose in 70% aqueous propanol) the polymer is filtered off and washed three times with 50 ml of methylene chloride each time. The combined filtrates are concentrated and the residue is dissolved in 20 ml of distilled water. This solution is acidified to pH 2 with 0.2N hydrochloric acid and extracted with ethyl acetate. The organic solution is dried over sodium sulfate and concentrated at room temperature. The remaining solid is dried overnight in vacuo over phosphorus pentoxide, the 3- (acetyloxymethyl) -7 - [[2- [4- (N, N-diethyldithiocarbamatomethyl) phenyl] -2-carboxyacetyl] amino] -8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid is obtained.

If, in the process of Example 33, the p- (N, N-diethyldithiocarbamatomethyl) phenylmalonic acid is replaced by the corresponding amount of an acid according to Table VIII, the following cephalosporin derivatives are obtained:

Table VII

Acid cephalosporin derivative

2-sulfo-p- (N, N-di-n-propyl- 3- (acetyloxymethyl) -7 - [[2-

thiocarbamatomethyl) phenyl- [4- (N, N-di-n-propyldithio-

acetic acid carbamatomethyl) phenyl] -2-

sulfoacetyl] amino] -8-oxo-5-

thia-1-azabicyclo [4.2.0] oct-

2-en-2-carboxylic acid

3- [p- (N, N-di-n-butyldithio- 3- (acetyloxymethyl) -7 - [[3-

carbamatomethyl) phenyl] -2- [4- (N, N-di-n-butyldithiocar-

sulfopropionic acid (bamatomethyl) phenyl] -2-sul-

fopropionyl] amino] -8-oxo-5-

thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VIII (cont.)

4- [p- (pyrrolidinodithio- 3- (acetyloxymethyl) -7 - [[4-

carbamatomethyl) phenyl] - [4- (pyrrolidinodithiocarbam-

2-sulfobutyric acid atomethyl) phenyl] -2-sulfo-

butyryl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-

en-2-carboxylic acid

p- (Piperidinodithiocarbam- 3- (acetyloxymethyl) -7 - [[3-

atomethyl) benzylmalonic acid [4- (piperidinodithiocarbam-

atomethyl) phenyl] -2-carboxy-

propionyl] amino] -8-oxo-5-

thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

p- (Morpholinodithiocarbam- 3- (acetyloxymethyl) -7 - [[4-

atomethyl) phenethylmalonic acid [4- (morpholinodithiocarbam-

atomethyl) phenyl] -2-carboxy-

butyryl] amino] -8-oxo-5-thia-

1-azabicyclo [4.2.0] oct-2-en-

2-carboxylic acid

2- [p- (monothiocarbamatomethyl) - 3- (acetyloxymethyl) -7 - [[4-

phenoxy] ethylmalonic acid [4- (monothiocarbamatomethyl) -

phenoxy] -2-carboxybutyryl] -

amino] -8-oxo-5-thia-1-azabi

cyclo [4.2.0] oct-2-en-2-carbon

acid

2- [p- (N, N-dimethylmonothio- 3- (acetyloxymethyl) -7 - [[4-

carbamatomethyl) phenyl] - [4- (N, N-dimethylmonothiocar-

thioethylmalonic acid (bamatomethyl) phenylthio] -2-

carboxybutyryl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

Table VIII (cont.)

p- (N, N-diethylmonothiocarbam- 3- (acetyloxymethyl) -7 - [[3-

atomethyl) anilinomethylmalon- [4- (N, N-diethylmonothiocar-

acid bamatomethyl) aniline] -2-car-

boxypropionyl] amino] -8-oxo-

5-thia-1-azabicyclo [4.2.0] -

oct-2-en-2-carboxylic acid

2- [5- (N, N-di-n-propylmonothio- 3- (acetyloxymethyl) -7 - [[2-

carbamatomethyl) -2-thienyl] - [5- (N, N-di-n-propylmono-

malonic acid thiocarbamatomethyl) -2-

thienyl] -2-carboxyacetyl] -

amino] -8-oxo-5-thia-1-aza-

bicyclo [4.2.0] oct-2-en-2-

carboxylic acid

2- [5- (N, N-di-n-butylmonothio- 3- (acetyloxymethyl) -7 - [[3-

carbamatomethyl) -2-thienyl] - [5- (N, N-di-n-butylmonothio-

malonic acid carbamatomethyl) -2-thienyl] -

2-carboxypropionyl] amino] -

8-oxo-5-thia-1-azabicyclo-

[4.2.0] oct-2-en-2-carbon

acid.

If corresponding amounts of an acid and a 7-aminocephalosporanic acid derivative according to Table IX are reacted with one another in the process of Example 18, the cephalosporin products also shown in Table IX are obtained:

Table IX

Table IX (cont.) Table IX (cont.) Table IX (cont.) Table IX (cont.)

If, in the process of Example 22, corresponding amounts of an acid with a protected amino group and a cephalosporin derivative according to Table X below are reacted with one another, the cephalosporin products also shown in Table X are obtained:

Table X

Table X (continued) Table X (continued)

If corresponding amounts of an acid derivative and a 7-aminocephalosporin derivative according to Table XI are reacted with one another in the process of Example 23, the cephalosporin products also shown in Table XI are obtained:

Table XI

Table XI (continued) Table XI (continued)

Example 24

3- (Acetyloxymethyl) -7 - [[2- [4- (dithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

(A) A mixture of 1 g of 3- (acetyloxymethyl) -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 1 g of p-chloromethylphenylacetyl chloride in 45 ml of ethyl acetate is refluxed for about 2 hours, then the solvent is removed in vacuo to give a yellow-brown amorphous product which is chromatographed on silica gel with benzene / acetone as the eluent. This gives 3- (acetyloxymethyl) -7 - [[2- [4- (chloromethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid with a melting point of 164 to 165 ° C (decomposition).

(B) A mixture of 1.09 g (2.5 millimoles) 3- (acetyloxymethyl) -7 - [[2- [4- (chloromethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1 -azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 2.2 g (20 millimoles) of ammonium dithiocarbamate in 40 ml of methanol is stirred in nitrogen for 5 hours, then the solvent is evaporated and there are 30 ml of cold water and 60 ml of ethyl acetate were added. The mixture is acidified to pH 2 with 10% aqueous hydrochloric acid, the organic phase is washed neutral with water and then dried over magnesium sulfate and concentrated. The residue is washed with ether and recrystallized from ethyl acetate, the 3- (acetyloxymethyl) -7 - [[2- [4- (dithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid is obtained.

In a similar manner, other compounds according to the invention can be prepared by adding the corresponding halomethyl-substituted acid according to Tables I, II, III or

Example 2, 3, 4, 6 or 7 with the corresponding 7-aminocephalosporin derivatives and then with a carbamate or carbamate salt of the formula wherein R, R [deep] 1 and R [deep] 2 have the meaning given for formula I, is converted.

Example 25

3- (Acetyloxymethyl) -7 - [[2- [4- (N, N-diethyldithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en -2-carboxylic acid-N-ethoxycarbonyl-N-methylaminomethyl ester

A mixture of 1.2 g of the sodium salt of 3- (acetyloxymethyl) -7 - [[2- [4- (N, N-diethyldithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 0.5 g of N-chloromethyl-N-methyl urethane in 40 ml of dimethylformamide is stirred at room temperature for 2 hours, then the mixture is poured into ice water and decanted. The oily residue is taken up in 75 ml of ethyl acetate, the solution is washed with 5 ml of dilute aqueous sodium bicarbonate solution and 15 ml of water, and then dried over magnesium sulfate, filtered and concentrated to give the title compound.

Example 26

3- (Acetyloxymethyl) -7 - [[2- [4- (morpholinodithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid -p-pivalyloxybenzyl ester

To a solution of 1.8 g of 3- (acetyloxymethyl) -7 - [[2- [4-

(morpholinodithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid hydrochloride in 25 ml of dimethylformamide are added 0.78 g of p-pivalyloxybenzyl alcohol , then it is cooled to 0 ° C. and then 3.7 mol of dicyclohexylcarbodiimide in 75 ml of dimethylformamide are added dropwise with stirring. The reaction mixture is stirred for 1 hour at 0 ° C. and for a further 4 hours at room temperature, then the dicyclohexylurea is filtered off. The filtrate is diluted with chloroform and washed with water. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo to give an oil which, after trituration with ether, gives the title compound.

Example 27

3- (Acetyloxymethyl) -7 - [[2- [4- (morpholinomonothiocarbamatomethyl) phenyl] -2- (5-indanyloxycarbonyl) acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-en-2-carboxylic acid

To 25.3 millimoles of 3- (acetyloxymethyl) -7 - [[2- [4- (morpholinomonothiocarbamatomethyl) phenyl] -2-carboxyacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-en-2-carboxylic acid in 35 ml of dioxane is added 6N hydrochloric acid to pH 2.5. Then 24.1 millimoles of N, N'-dicyclohexylcarbodiimide in 35 ml of dioxane are added and the mixture is stirred at room temperature for 15 to 20 minutes, after which 24.1 millimoles of 5-indanol are added. The resulting mixture is stirred for 4 hours, the N, N'-dicyclohexylurea formed is filtered off and the filtrate is extracted three times with methyl isobutyl ketone. The organic extract is washed with water, dried over magnesium sulfate and concentrated to dryness in vacuo to give the title compound.

Example 28

3 - [(2-methyl-1,3,4-thiadiazol-5-ylthio) methyl] -7 - [[2- [4- (dithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia- 1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

A solution of 3 millimoles of 3 - [(acetyloxymethyl) -7- [2- [4- (dithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- En-2-carboxylic acid in 100 ml of water is treated with 3 millimoles of sodium bicarbonate and 6 millimoles of 2-methyl-1,3,4-thiadiazol-5-ylthiol at 70 ° C. under nitrogen for 3 1/2 hours. The water is removed in vacuo and the residue is taken up in methanol. A large excess of acetonitrile is added to precipitate the product, then the product is filtered off and dried in a vacuum desiccator to give the title compound.

In the same way, other compounds according to the invention in which the 3-position of the cephalosporin ring is substituted by a heterocyclic thiomethyl compound can be prepared from the relevant 3- (acetyloxymethyl) -substituted cephalosporin compound by reaction with the thiol as described above.

Claims (36)

1. Compound of formula wherein R [deep] 1 and R [deep] 2 are each hydrogen or lower alkyl radicals with 1 to 4 carbon atoms or NR [deep] 1R [deep] 2 together a pyrrolidino, piperidino or morpholino radical, R oxygen or sulfur, aryl denotes phenyl - Or 2-thienyl radical, Y hydrogen, chlorine, bromine, a straight-chain or branched lower alkyl radical having 1 to 4 carbon atoms or lower alkoxy radical having 1 to 4 carbon atoms, with the proviso that when aryl is the 2-thienyl radical, Y is hydrogen , Z is a bond, oxygen, sulfur or the imino group, with the proviso that when aryl is the 2-thienyl radical, Z is a bond, W is hydrogen, the methyl, amino, hydroxy or sulfonic acid group or a radical COOR [ deep] 3, in which R [deep] 3 is hydrogen or the 5-indanyl radical, n is the number 0, 1 or 2, with the proviso that if W are different from hydrogen or methyl and Z is not a bond, n is not 0 means, R [deep] 4 is hydrogen or the methoxy group, M is water toff, a pharmaceutically acceptable non-toxic cation, an alkanoyloxymethyl radical with an alkanoyl portion with 1 to 5 carbon atoms, which can be straight-chain or branched, an alkanoylaminomethyl radical with an alkanoyl portion with 1 to 5 carbon atoms, which can be straight-chain or branched, with the amine nitrogen through an alkyl radical with 1 to 4 carbon atoms can be substituted, an alkoxycarbonylaminomethyl radical with an alkoxy moiety with 1 to 4 carbon atoms, which can be straight-chain or branched, the amine nitrogen can be substituted by an alkyl radical with 1 to 4 carbon atoms, a p-alkanoyloxybenzyl radical with an alkanoyl moiety with 1 to 5 carbon atoms, which can be straight-chain or branched, or an aminoalkanoyloxymethyl radical with an alkanoyl moiety with 2 to 15 carbon atoms, wherein the amine nitrogen can be mono- or disubstituted by a lower alkyl radical with 1 to 4 carbon atoms, and X is hydrogen, acetoxy-, 1,3,4-thiadiazol-5-ylthio-, 3-methyl-1,2,4-thiadiazol-5-ylthio-, tetrazol-5-ylthio-, 1-methyltetrazol-5- represent ylthio, 2-methyl-1,3,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,2,3-triazol-5-ylthio radical, and their pharmaceutically acceptable salts. 2. A compound according to claim 1, wherein aryl is the phenyl radical. 3. A compound according to claim 2, wherein R [deep] 4 is cis. 4. A compound according to claim 1, wherein aryl is the 2-thienyl radical. 5. A compound according to claim 4, wherein R [deep] 4 is cis. 6. A compound according to claim 1, wherein W is hydrogen. 7. A compound according to claim 6, wherein Z is a bond. 8. A compound according to claim 6, wherein Z is oxygen or sulfur. 9. A compound according to claim 6, wherein Z is the imino group. 10. A compound according to claim 1, wherein W is the methyl radical. 11. A compound according to claim 10, wherein Z is a bond. 12. A compound according to claim 10, wherein Z is oxygen or sulfur. 13. A compound according to claim 10, wherein Z is the imino group. 14. A compound according to claim 1, wherein W is the hydroxyl group. 15. A compound according to claim 14, wherein Z is a bond. 16. A compound according to claim 14, wherein Z is oxygen or sulfur. 17. A compound according to claim 14, wherein Z is the imino group. 18. A compound according to claim 1, wherein W is the amino group. 19. The compound of claim 18, wherein Z is a bond. 20. A compound according to claim 18, wherein Z is oxygen or sulfur. 21. A compound according to claim 18, wherein Z is the imino group. 22. A compound according to claim 1, wherein W denotes the radical COOR [deep] 3 or the sulfonic acid group. 23. A compound according to claim 22, wherein Z is a bond. 24. A compound according to claim 22, wherein Z is oxygen or sulfur. 25. A compound according to claim 22, wherein Z is the imino group. 26. Compound of Formula where R is oxygen or sulfur, R [deep] 1 and R [deep] 2 are each hydrogen or lower alkyl radicals with 1 to 4 carbon atoms or NR [deep] 1R [deep] 2 is a pyrrolidino, piperidino or morpholino radical, W 'is hydrogen, the hydroxyl group, amino group, carboxyl group or sulfonic acid group and X 'represent hydrogen, the acetoxy, 3-methyl-1,2,4-thiadiazol-5-ylthio or 1-methyltetrazol-5-ylthio radical, the hydrogen atoms in 6- and 7-position cis to each other, and their pharmaceutically acceptable salts. 27. A compound according to claim 26, wherein X 'is the acetoxy radical. 38. 3- (Acetyloxymethyl) -7 - [[2- [4- (diethyldithiocarbamatomethyl) phenyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid and its pharmaceutically acceptable salts. 29. 3- (Acetyloxymethyl) -7 - [[2- [4- (dithiocarbamatomethyl) phenyl] -2-hydroxyacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid and its pharmaceutically acceptable salts. 30. 3- (Acetyloxymethyl) -7 - [[2- [4- (morpholinodithiocarbamatomethyl) phenyl] -2-aminoacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid and its pharmaceutically acceptable salts. 31. 3- (Acetyloxymethyl) -7 - [[2- [4- (morpholinomonothiocarbamatomethyl) phenyl] -2-carboxyacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid and its pharmaceutically acceptable salts. 32. 3-Methyl-7- [2- [4- (dithiocarbamatomethyl) phenyl] -2-aminoacetyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and their pharmaceutically acceptable salts. 33. Process for the preparation of a compound according to claim 1, wherein R [deep] 3 is hydrogen, characterized in that a derivative of the formula where halo is chlorine or bromine and W [high] 2 is hydrogen, the methyl group, amino group, hydroxyl group, sulfonic acid or carboxyl group and aryl, Y, Z, n, R [deep] 4 and M are as defined above, in a solvent at a temperature of 0 to 125 ° C for 1/2 to 24 hours with a compound of the formula or a salt thereof, in which R, R [deep] 1 and R [deep] 2 have the meaning given above, and, if W [high] 2 denotes the amino group, protects it from the reaction with a suitable protective group, which then is removed by acid hydrolysis. 34. A process for the preparation of a compound according to claim 1, wherein R [deep] 3 is the 5-indanyl radical, characterized in that the compound in question, in which R [deep] 3 is hydrogen, in an inert solvent in the presence of N. Reacts, N'-dicyclohexylcarbodiimide at a pH of about 2.5 and a temperature of 20 to 30 ° C with 5-indanol. 35. Process for the preparation of a compound according to claim 1, wherein R [deep] 3 is hydrogen, characterized in that a derivative of the formula wherein R [deep] 4, M and X have the meaning given above, with an acid of the formula wherein W [high] 2 is hydrogen, the methyl, amino, hydroxy, sulfonic acid or carboxyl group and R, R [low] 1, R [low] 2, Y, aryl, Z and n are as defined in claim 1 own, or a functional derivative thereof in a solvent and optionally in the presence of a base from an alkali metal bicarbonate at -10 to 100 ° C for 30 minutes to 10 hours, with the proviso that, if W [high] 2 is the amino group, this is protected from the coupling reaction by a suitable protective group and then removed by acid hydrolysis. 36. Process for the preparation of a compound of the formula wherein aryl, Y, R, R [deep] 1, R [deep] 2, Z, n, W and R [deep] 4 have the meaning given in claim 1 and -S-hetero denotes 1,3,4-thiadiazole -5-ylthio-, 3-methyl-1,2,4-thiadiazol-5-ylthio-, tetrazol-5-ylthio-, 1-methyltetrazol-5-ylthio-, 2-methyl- 1,3,4-oxadiazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,2,3-triazol-5-ylthio radical, and their pharmaceutically acceptable salts, thereby characterized in that one equivalent of a derivative of the formula wherein R, R [deep] 1, R [deep] 2, Y, aryl, Z, n, W and R [deep] 4 have the meaning given in claim 1, and dissolve in water at 25 to 90 ° C under a nitrogen atmosphere 1 equivalent of a base such as triethylamine or sodium bicarbonate and 1 to 3 equivalents of a heterothiol of the formula HS-hetero are added, whereupon the reaction mixture is stirred at a temperature of 25 to 90 ° C. for about 2 to 6 hours.